Interpretive Summary: Serotonin (5-hydroxytriptamine, 5-HT) is a neurotransmitter that regulates food intake, energy expenditure, and glucose homeostasis via actions within the central nervous system. We showed that serotonin activates a selective population of cells in the brain (POMC neurons) through its receptor, serotonin 2C receptor. Activation of this receptor opens ion channels, called TRPC, which results in firing of POMC neurons. Ultimately, this leads to inhibition of food intake.

Technical Abstract:
Serotonin 2C receptors (5-HT2CRs) expressed by pro-opiomelanocortin (POMC) neurons of hypothalamic arcuate nucleus regulate food intake, energy homeostasis ,and glucose metabolism. However, the cellular mechanisms underlying the effects of 5-HT to regulate POMC neuronal activity via 5-HT2CRs have not yet been identified. In the present study, we found the putative transient receptor potential C (TRPC) channels mediate the activation of a subpopulation of POMC neurons by mCPP(a 5-HT2CR agonist). Interestingly, mCPP-activated POMC neurons were found to be a distinct population from those activated by leptin. Together, our data suggest that 5-HT2CR and leptin receptors are expressed by distinct subpopulations of arcuate POMC neurons and that both 5-HT and leptin exert their actions in POMC neurons via TRPC channels.